1. Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.
- Author
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Zhaohui Wang, Shiyuan Huang, Yuling Sheng, Xu Peng, Hui Liu, Nan Jin, jun Cai, Yanwen Shu, Ting Li, Ping Li, Cheng Fan, Xiaofan Hu, Wenyong Zhang, Rui Long, Ya You, Caihong Huang, Yi Song, Chunhua Xiang, Jue Wang, and Yong Yang
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MYOCARDIAL infarction , *TOPIRAMATE , *MONOCYTES , *MACROPHAGES , *COLLAGEN - Abstract
Aims: Monocytes/macrophages response plays a key role in postinfarction inflammation that contributes greatly to postinfarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAa receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (Ml). Methods and results:After Ml was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with and results one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after Ml, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, proinflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiography indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. Conclusion: Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for Ml therapy in the future. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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